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J. Biol. Chem., Vol. 283, Issue 5, 2631-2643, February 1, 2008

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Phosphatidylinositol 3-Kinase Activation Is Required for Stress Protocol-induced Modification of Hippocampal Synaptic Plasticity^*

Ping-Chun Yang, Chih-Hao Yang, Chiung-Chun Huang, and Kuei-Sen Hsu¹

From the Department of Pharmacology, College of Medicine, and the Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 701, Taiwan

Stress dramatically affects the induction of hippocampal synaptic plasticity; however, the molecular details of how it does so remain unclear. Phosphatidylinositol 3-kinase (PI3K) signaling plays a crucial role in promoting neuronal survival and neuroplasticity, but its role, if any, in stress-induced alterations of long term potentiation (LTP) and long term depression (LTD) is unknown. We found here that inhibitors of PI3K signaling blocked the effects of acute restraint-tail shock stress protocol on LTP and LTD. Therefore, the purpose of the present study is to explore the signaling events involving PI3K in terms of its role in mediating stress protocol-induced alterations of LTP and LTD. We found that stress protocol-induced PI3K activation can be blocked by various inhibitors, including RU38486 for glucocorticoid receptors, LY294002 for PI3K, and DL-2-amino-5-phosphonopentanoic acid for N-methyl-D-aspartate receptors or brain-derived neurotrophic factor antisense oligonucleotides. Also, immunoblotting analyses revealed that stress protocol induced a profound and prolonged phosphorylation of numbers of PI3K downstream effectors, including 3-phosphoinositide-dependent protein kinase-1, protein kinase B, mammalian target of rapamycin (mTOR), p70 S6 kinase, and eukaryotic initiation factor 4B in hippocampal CA1 homogenate, which was prevented by the PI3K inhibitor pretreatment. More importantly, we found that stress protocol significantly increased the protein expression of dendritic scaffolding protein PSD-95 (postsynaptic density-95), which is known to be involved in LTP and LTD, in an mTOR-dependent manner. These results identify a key role of PI3K signaling in mediating the stress protocol-induced modification of hippocampal synaptic plasticity and further suggest that PI3K may do so by invoking the protein expression of PSD-95.

Received for publication, August 20, 2007 , and in revised form, December 4, 2007.

^* This work was supported by National Health Research Institute Grant NHRI-EX96-9618NI and National Science Council, Taiwan, Grant NSC96-2752-B-006-002-PAE. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan 701, Taiwan. Tel.: 886-6-2353535 (ext. 5498); Fax: 886-6-2749296; E-mail: richard{at}mail.ncku.edu.tw.

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